Structural insights into PPP2R5A degradation by HIV-1 Vif.

Autor: Hu Y; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA., Delviks-Frankenberry KA; Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA., Wu C; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA., Arizaga F; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA., Pathak VK; Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA. vinay.pathak@nih.gov., Xiong Y; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA. yong.xiong@yale.edu.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Oct; Vol. 31 (10), pp. 1492-1501. Date of Electronic Publication: 2024 May 24.
DOI: 10.1038/s41594-024-01314-6
Abstrakt: HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the regulatory subunits PPP2R5(A-E) of cellular protein phosphatase 2A to induce G2/M cell cycle arrest. As PPP2R5 proteins bear no functional or structural resemblance to A3s, it is unclear how Vif can recognize different sets of proteins. Here we report the cryogenic-electron microscopy structure of PPP2R5A in complex with HIV-1 Vif-CBFβ-elongin B-elongin C at 3.58 Å resolution. The structure shows PPP2R5A binds across the Vif molecule, with biochemical and cellular studies confirming a distinct Vif-PPP2R5A interface that partially overlaps with those for A3s. Vif also blocks a canonical PPP2R5A substrate-binding site, indicating that it suppresses the phosphatase activities through both degradation-dependent and degradation-independent mechanisms. Our work identifies critical Vif motifs regulating the recognition of diverse A3 and PPP2R5A substrates, whereby disruption of these host-virus protein interactions could serve as potential targets for HIV-1 therapeutics.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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